CAROLINA: Linagliptin, glimepiride show similar CV safety in lower-risk type 2 diabetes
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Adults with early type 2 diabetes and elevated cardiovascular risk who were assigned the DPP-IV inhibitor linagliptin were no more likely to experience a CV event during 6 years of follow-up than similar adults assigned the sulfonylurea glimepiride, according to study data presented at the European Association for the Study of Diabetes annual meeting.
In presenting findings from CAROLINA, the longest duration CV outcomes trial to date and the first head-to-head CV outcomes trial for a DPP-IV inhibitor vs. a sulfonylurea, the researchers noted the findings also “vindicate” glimepiride, which comes with an FDA warning for increased CV mortality risk. Initial findings were first presented at the American Diabetes Association Scientific Sessions in June.
“Other than a cost consideration, we can say that CAROLINA supports the use of a DPP-IV inhibitor before a sulfonylurea,” Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City and clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, said during a presentation. “CV safety should no longer be a consideration in the decision process for selecting between either of these two oral agents. On the other hand, we feel that this data reaffirms the current clinical recommendations to choose an agent after metformin based on proven CV benefit, which none of these agents provides.”
The study was designed to provide “definitive evidence” regarding the CV and hypoglycemia safety of linagliptin (Tradjenta, Boehringer Ingelheim/Eli Lilly) vs. glimepiride to be considered in the decision-making process of selecting a second oral agent to add to metformin early in type 2 diabetes, Rosenstock said.
“In the decision-making process for selecting an agent, a DPP-IV is listed when you want to avoid hypoglycemia, when you want to avoid weight loss, but sulfonylureas continue to have a role if cost is a major consideration,” Rosenstock said. “Indeed, sulfonylureas are used around the world by 45% to 50% of people with type 2 diabetes.”
Study design
Rosenstock and colleagues analyzed data from 6,033 adults aged 40 to 85 years with type 2 diabetes, recruited from 607 sites in 43 countries between 2010 and 2018 (median diabetes duration, 6.2 years). Participants had established CVD or increased risk for CVD. Researchers randomly assigned participants to 5 mg linagliptin once daily (n = 3,023) or a daily dose of up to 4 mg glimepiride (n = 3,010) as add-on therapy to any prescribed diabetes medications for a median of 6.3 years. Primary outcome was a composite of CV death, nonfatal myocardial infarction and nonfatal stroke.
Researchers determined there were no between-group differences with respect to CV events. The HR for the primary outcome was 0.98 (95% CI, 0.84-1.14). Corresponding HRs for CV mortality and non-CV mortality were 1 (95% CI, 0.81-1.24) and 0.82 (95% CI, 0.66-1.03), respectively. There was no between-group difference for HbA1c.
Researchers noted that participants in the glimepiride group experienced modest weight gain vs. participants assigned linagliptin (between-group difference, –1.5 kg; 95% CI, –1.8 to –1.3) and experienced greater incidence of investigator-reported hypoglycemia (37.7% vs. 10.6%), for an HR for hypoglycemia of 0.23 for linagliptin vs. glimepiride (95% CI, 0.21-0.26), or a number needed to treat of three over 6 years. Patients in the glimepiride group also experienced more severe hypoglycemia vs. those assigned linagliptin (2.2% vs. 0.3%).
Adverse events occurred for 2,822 participants in the linagliptin group (93.4%) and 2,856 in the glimepiride group (94.9%), with 15 participants in the linagliptin group vs. 16 in the glimepiride group experiencing confirmed acute pancreatitis.
‘Revisit’ glimepiride
The findings from CAROLINA complement those presented from the CARMELINA trial at EASD 2018, Darren K. McGuire, MD, MHSc, professor of medicine in the division of cardiology, Dallas Heart Ball Chair for Research on Heart Disease in Women and Distinguished Teaching Professor at the University of Texas Southwestern Medical Center, Dallas, said during a presentation on the study’s clinical implications.
Findings from CARMELINA demonstrated that linagliptin was safe for adults with type 2 diabetes, established CVD and/or chronic kidney disease when compared with placebo, with a neutral effect for hospitalization for heart failure and kidney outcomes. In CARMELINA, McGuire said, 57% of participants had established atherosclerotic CVD.
“We should interpret the CAROLINA trial results in the context of what we have already demonstrated with respect to the CV safety of linagliptin vs. placebo in the CARMELINA trial,” McGuire said during his presentation. “We now have bookended the disease spectrum, studying in CARMELINA high-risk, advanced-disease patients with type 2 diabetes, and now in CAROLINA, a low-risk, earlier in disease course patient population.”
Sulfonylureas have limitations, McGuire said, including increased risk for hypoglycemia and weight gain and limited glycemic durability over time, as well as a lingering concern regarding the class’ long-term CV safety dating back to research conducted in the 1960s.
“Now we have data in hand ... proving CV safety and, importantly, analyzing 340 CV death events, a robust statistical sample, so we can prove with great precision and certainty that there is no incremental CV risk associated with glimepiride when compared with linagliptin,” McGuire said. “On the backdrop of linagliptin’s proven CV safety against placebo, we can deduct indirectly CV safety about glimepiride.”
What CAROLINA does not do is assuage the concerns for all sulfonylureas, McGuire said.
“Whether this extends to other, modern sulfonylureas, and to other patient populations, we cannot draw conclusions, he said. “Based on the totality of the data from CAROLINA and CARMELINA, the FDA should revisit the glimepiride product label warnings for increased CV mortality.”
Philip Home, DPhil, MRCP, DM , professor of diabetes medicine at Newcastle University, U.K., called CAROLINA a “good and very relevant study,” performed in a group of people highly relevant to typical ambulatory care, unlike many recent diabetes CV outcomes trials. Follow-up for CAROLINA was appropriate to detect adverse events for a therapy likely to be used long term, Home said, and the study population was racially diverse with 17.6% of participants Asian.
“Taken with the results of CARMELINA, linagliptin is unable to match the CV protection that we have from the GLP-1 receptor agonists in people with CVD, or match the renal or HF protection with the SGLT2 inhibitors in those at risk, but those groups are 20% of the people we see in the clinic,” Home said. “Here, you can choose between a drug which doesn’t have a hypoglycemia tolerability problem and a drug which does on the basis of this evidence.” – by Regina Schaffer
References:
Rosenstock J, et al. Results and implications of CAROLINA comparing linagliptin vs. glimepiride. Presented at: European Association for the Study of Diabetes Annual Meeting; Sept. 16-20, 2019; Barcelona, Spain.
Rosenstock J, et al. JAMA. 2019;doi:10.1001/jama.2019.13772.
Disclosures: Boehringer Ingelheim and Eli Lilly sponsored the CAROLINA study. Home reports he has received funding for lectures, advisory boards and research activities from Boehringer Ingelheim. McGuire reports he is a consultant for Afimmune, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Metavant, Merck and Novo Nordisk. Rosenstock reports he has received research and other financial support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Bukwang, Eli Lilly, Genentech, GlaxoSmithKline, Intarcia, Janssen, Lexicon, Melior Pharmaceuticals, Merck, Novo Nordisk, Oramed, PegBio Co., Pfizer and Sanofi